A New 12q21 Deletion Syndrome: A Case Report and Literature Review

Diagnosis in children with physical and intellective anomalies is very challenging because of the wide spectrum of causes. Array-based comparative genomic hybridization (CGH) has acquired an important role in pediatric diagnostic work up. Interstitial deletion of the long arm of chromosome 12 are rare. To date, deletions including the 12q21 region were reported in only 13 patients. The main features are development delay, eyes and central nervous system anomalies, and heart and kidney defects. We describe a 3-year-old boy with a de novo 15 Mb deletion at 12q21.1q21.32, never reported in the last cases. By screening the critical region and reviewing the literature, we identified SYT1, PPP1R12A, and CEP290 such as pathogenetic genes.


Introduction
Diagnosis in children with physical and cognitive impairment is very challenging because of the wide number of etiological events. Array-based comparative genomic hybridization (CGH) has acquired an important role in diagnostic work up allowing a better definition of the diagnosis. Deletions in the 12q21 region has been rarely reported and so far only 13 cases with this anomaly have been published. We report a 3,1/2years-old boy with development delay, craniofacial dysmorphism, strabismus, muscle mass hypotrophy, pectoral muscle asymmetry, scoliosis, and dysmorphic corpus callosum at the brain MRI. The CGH microarray and height, always under 3rd centile. Developmentally, he achieved head support at the age of 5 months, he was able to sit unsupported at the age of 9 months, and walked unsupported at 30 months. His examination reveals prominent forehead, hypertelorism, strabismus, triangular face, low set ears, hypoplastic nostrils, and micro-and retrognathia (►Fig. 1). We noted poor muscle weight, asymmetry of the pectoral muscle (left > right), and scoliosis. Control of the sphincters not yet acquired. He is socially responsive, with delayed speech and motor impediment to fine and coarse motor skills. Brain magnetic resonance imaging (MRI) revealed a dysmorphic corpus callosum (►Fig. 2). Array-based comparative genomic hybridization (CGH) of DNA extracted from Fig. 1 The main clinical features reported in 12q21 deletion children. The imagine was made taking inspiration from our patient and others affected by similar deletion, whose photos are published in the literature. 1,3,8,11,12  peripheral blood revealed an interstitial deletion of 12q21.1q21.32. The anomaly was 15 Mb. The analysis on his parents was negative.

Discussion
The first to describe an interstitial deletion of the long arm of chromosome 12 was Meinecke's in the 1987, describing a syndrome with multiple malformations including cleft lip and palate and cardiac abnormalities in 12q13.3q21.1 deletion. 1 Two years later, Watson et al described a 12q15q21.2 deletion in a child with physical abnormalities and development delay. 2 Thirty-two years have passed since these first report;: the reports on this topic increased after the introduction of array-based CGH examination which allowed researchers to extend the phenotype of this disorder. Several molecular mutations have been reported in other patients. [1][2][3][4][5][6][7][8][9][10][11][12] Common features included development delay, clinical dysmorphism, heart defects, and anomalies in the central nervous system. Most of the 12q21 deletion syndrome cases reported in the literature involve the SYT1, PPP1R12A, and CEP290 genes.
We compared the phenotype with the data available in the publica database DECIPHER (►Fig. 3). The main characteristic in common with our child were developmental delay, musculoskeletal abnormalities, and corpus callosum anomalies. A previous study, published in 2020 by Niclass et al described two candidate genes as critical component   of the deletion: SYT1 and PPP1R12A. 11 SYT1 encodes an integral membrane protein of postsynaptic vesicles thought to serve as Ca 2þ sensors in the process of vesicular trafficking and exocytosis. 13 Mutations in the SYT1 cause neurodevelopment disorder described in a rare syndrome, Baker-Gordon syndrome. They reported 11 individuals affected by infantile hypotonia, congenital ophthalmic abnormalities, childhoodonset hyperkinetic movements disorder, motor stereotypies, and developmental delay. In addition, SYT1 is included as a syndromic gene for the autism spectrum disease in the SFARI database (►Fig. 3). Although the patient herein reported carries a very large deletion, the phenotype is consistent with that described in the work by Niclass et al. It underlines that a small region, including the candidate-genes SYT1 and PPP1R12A, can be considered critical and sufficient for the clinical manifestations of 12q21 microdeletion syndrome. PPP1R12A encodes a regulatory subunit of myosin phosphatase. This enzyme is recently associated in the cellular processes such as cell cycle, gene expression regulation, neurotransmitter release, and even embryonic development. 14 We suppose also CEP290 as one of the main genes for our child. In the literature, there are suggestive evidence in autism reports (►Fig. 4). Although the molecular function is playing a role in ciliary transport processes, defects in this gene are associated with several neurologic diseases, for example Joubert's syndrome, Leber's congenital amaurosis, or Meckel's syndrome 15 (►Tables 1 and 2).

Ethical Approval
This study was conformed to the ethical guidelines of Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Authors' Contributions
Each author committed a substantial contribution to the conception or design of the work and to revise it critically for important intellectual content. In addition, each author approved the final version to be published. Conversely, each author agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding
None.

Conflict of Interest
None declared.